Combination dosage form of a mu opioid receptor antagonist and an opioid agent

ABSTRACT

The invention provides a solid composition of the peripheral mu opioid antagonist axelopran and a combination dosage form of the mu opioid antagonist axelopran sulfate in an immediate release form and an opioid analgesic agent which may be in an extended release, sustained release, modified release, or controlled release form and methods of preparing such a combination dosage form.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/141,981, filed on Apr. 2, 2015 the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention

The invention is directed to a solid composition of a peripheral muopioid receptor antagonist and to a combination of the mu opioidreceptor antagonist composition and an opioid analgesic agent. Inparticular, the invention is directed to a unit dosage form in which themu opioid receptor antagonist is in an immediate release form and theopioid analgesic agent may be in an extended release, sustained release,modified release, or controlled release form and to methods of preparingsuch a unit dosage form.

State of the Art

Compounds which function as agonists at opioid receptors, of whichoxycodone, hydrocodone, morphine, and oxymorphone are common examples,are the mainstays of analgesic therapy for the treatment of moderate tosevere pain. It is understood that opioid analgesics exert theirbeneficial effect chiefly by activation of mu opioid receptors in thebrain and central nervous system. However, opioid receptors areexpressed throughout the body, both in the central nervous system and inperipheral regions including the gastrointestinal (GI) tract.Unfortunately, adverse side effects of the use of opioid analgesics maybe caused by activation of these peripheral receptors. In particular,patients receiving opioids analgesics for short or long term painmanagement frequently experience a range of adverse gastrointestinalsymptoms, in particular opioid induced constipation (OIC). Encompassingconstipation, delayed gastric emptying, abdominal discomfort, andnausea, OIC can be extremely debilitating and is not prone to tolerance.Gastrointestinal symptoms may be severe enough to seriously compromisepain management for some patients.

Peripherally acting opioid antagonist compounds that do not readilycross the blood-brain barrier have been shown to be beneficial incounteracting opioid-induced constipation. In particular, axelopran,3-((1R,3r,5S)-8-(2-((cyclohexylmethyl)((2S)-2,3-dihydroxypropanoyl)amino)ethyl)-8-azabicyclo[3.2.1]octan-3-yl)benzamide,

(U.S. Pat. Nos. 7,622,508 and 7,943,772) has been demonstratedclinically to ameliorate the symptoms of OIC in non-cancer pain patientson a stable opioid regimen without compromising analgesia. (Vickery etal. Pain Week 2012, Las Vegas, Nev. (P-87).

Patients taking opioid analgesics for pain management may find it usefulto also take a peripheral opioid antagonist to manage adverse sideeffects of their pain medication. Such patients, who may be sufferingfrom a variety of serious conditions, frequently are also prescribedadditional drugs and thus are burdened with managing a complicatedpharmaceutical regimen. Therefore, it may be desirable to combinemultiple drugs in a combination dosage form for ease of administrationand improved therapeutic compliance. In particular, use of a combinationof a peripheral opioid antagonist, such as axelopran, and an opioidagonist may address concerns of OIC before they develop.

Depending on the clinical need, opioid analgesics can be administeredthrough oral, transdermal and parenteral routes for either chronic oracute use, of which oral administration is commonly preferred. Whileimmediate release opioids provide efficacious pain management,especially for acute and break-through pain, controlled or extendedrelease opioids have demonstrated significant clinical value. However,the prophylactic effect of a peripheral opioid antagonist is typicallyachieved by immediate release of the antagonist agent. It would bedesirable to provide a dosage form that combines a peripheral opioidantagonist in an immediate release form with an opioid analgesic agentthat may be in an immediate release or in a modified (controlled orextended or sustained) release dosage form.

However, there are several technical problems that can arise whencombining a peripheral opioid antagonist with an opioid analgesic agent.First, the peripheral opioid antagonist must be sufficiently stableduring storage of the dosage form. For example, axelopran is known todegrade due to oxidation in its amorphous form. Additionally, theperipheral opioid antagonist should not significantly affect the releaseprofile or other properties of the opioid analgesic agent.

SUMMARY OF THE INVENTION

The present invention provides a combination dosage form comprising aperipheral mu opioid receptor antagonist, such as axelopran, in animmediate release form and an opioid analgesic agent in a solid dosageform presented either in an immediate release or a modified releaseform. In one aspect, the present invention relates to a drug overcoatformulation comprising axelopran in an immediate release formulation andto a method of preparing such a drug over-coated opioid combinationproduct.

Axelopran has been shown to be stable as the crystalline sulfate saltwhile amorphous axelopran is known to be insufficiently stable for usein a drug product. The present invention is made possible by thediscovery of the key requirements for the conversion of amorphousaxelopran to crystalline axelopran during or after any drug productpreparation process that may initially form amorphous axelopran.Specifically, by the judicious choice of excipients and relative ratioof excipients to axelopran and, optionally, further by control ofprocess conditions, a solid composition comprising axelopran sulfate incrystalline form with desirable physical properties may be prepared.

In one aspect, therefore, the invention provides a solid compositioncomprising axelopran sulfate and a film forming polymer. In one aspect,the film forming polymer is polyvinyl alcohol. In one aspect, the solidcomposition further comprises a plasticizer and optionally anantioxidant. In one aspect, the plasticizer is polyethylene glycol 3350and the antioxidant is ascorbic acid. In one aspect, the solidcomposition comprises

(a) between about 50% and about 95% by weight axelopran sulfate,

(b) between about 5% and about 50% by weight polyvinyl alcohol,

(c) between about 0% and about 45% polyethylene glycol 3350, and

(d) between about 0% and about 10% ascorbic acid.

In one aspect, the solid composition of the invention comprisesaxelopran sulfate in crystalline form. In one aspect the solidcomposition comprising crystalline axelopran sulfate is stable uponstorage at accelerated conditions for about 3 months. The solidcomposition may form a solid bead or may serve as a film or coating onan inert solid tablet or on a solid dosage form.

The ability to provide formulations that can controllably convertamorphous axelopran to a stable crystalline form has broad utility forthe development of stable combination products. Commercial opioidproducts as well as those in development have resulted from significantresearch effort to provide modified release, as well as abuse-deterrent,properties. The present approach allows axelopran to be combined withthe broad range of opioid products currently on the market or indevelopment without significantly affecting the release profile orabuse-deterrent properties of the opioid analgesic agent.

In one aspect, the combination dosage form comprises axelopran or apharmaceutically acceptable salt thereof as an active coating layer,equivalently termed a drug overcoat layer, on an opioid analgesic dosageform. In one aspect, the active coating layer comprises the solidcomposition of the invention. Thus, in one aspect, the active coatinglayer comprises axelopran sulfate and a film forming polymer. In anotheraspect, the active coating layer comprises axelopran sulfate, a filmforming polymer, a plasticizer, and optionally an antioxidant. In afurther aspect, the active coating layer comprises axelopran sulfate ina crystalline form. Optionally, the combination dosage form furthercomprises a subcoat layer between the active coating layer and theopioid dosage form.

In one aspect, the dosage form of the invention provides the benefit ofa combination product that enables immediate release of a peripheral muopioid receptor antagonist without affecting the drug releasecharacteristics of an opioid analgesic agent from a modified (controlledor extended or sustained) release dosage form and further withoutaffecting pharmacokinetic characteristics of each drug component.

Axelopran has been shown to be effective at ameliorating the symptoms ofopioid-induced constipation at low dosages. In one aspect, the inventionprovides a combination dosage form comprising between about 2 mg andabout 30 mg of axelopran in an immediate release formulation and anopioid analgesic agent in a modified release form. In one aspect, theopioid analgesic dosage form comprises oxycodone hydrochloride oroxymorphone hydrochloride.

In one aspect, the invention provides a method of treating pain in amammal, the method comprising administering to the mammal a combinationdosage form comprising a peripheral mu opioid receptor antagonistovercoated on an opioid analgesic agent. In one aspect the peripheral muopioid receptor antagonist in the combination dosage form is axelopranor a pharmaceutically acceptable salt thereof. In another aspect, theperipheral mu opioid receptor antagonist in the combination dosage formis axelopran sulfate.

In one aspect, the invention provides a method of ameliorating agastrointestinal side effect of opioid analgesic therapy, the methodcomprising administering the combination dosage form of axelopran or apharmaceutically acceptable salt thereof and an opioid analgesic agent.

In a further aspect, the invention provides a method of forming thecombination dosage form of the invention, the method comprisingproviding an opioid analgesic agent in a solid dosage form and coatingthe solid dosage form with a coating layer comprising axelopran or apharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B show the percentage of drug (axelopran and oxycodonehydrochloride) dissolved as a function of time of a combination dosageform of axelopran (10 mg label claim) and oxycodone hydrochloridecontrolled-release tablet (20 mg label claim) for axelopran drugovercoat Formulation A and axelopran drug overcoat Formulation B,respectively.

FIG. 2A and FIG. 2B show the percentage of drug (axelopran andoxymorphone hydrochloride) dissolved as a function of time of acombination dosage form of axelopran (10 mg label claim) and oxymorphonehydrochloride extended release tablet (10 mg label claim) for axeloprandrug overcoat Formulation A and axelopran drug overcoat Formulation B,respectively.

FIG. 3A and FIG. 3B show the mean plasma concentration±standarddeviation (ng/mL) as a function of time of oxycodone hydrochloride andaxelopran, respectively from a single dose pharmacokinetic study inbeagle dogs administered the combination dosage form of axelopran andoxycodone hydrochloride, co-administered the two components asindividual tablets, and administered the components individually.

FIG. 4A and FIG. 4B show the mean plasma concentration±standarddeviation (ng/mL) as a function of time of oxymorphone hydrochloride andaxelopran, respectively, from a single dose pharmacokinetic study inbeagle dogs administered the combination dosage form of axelopran andoxymorphone hydrochloride, co-administered the two components asindividual tablets, and administered the components individually.

FIG. 5 shows the mean oxycodone plasma concentration±standard deviation(ng/mL) as a function of time from a single dose pharmacokinetic studyin healthy human subjects administered the combination dosage form ofaxelopran and oxycodone hydrochloride, co-administered the twocomponents as individual tablets and administered the componentsindividually.

FIG. 6 shows the mean axelopran plasma concentration±standard deviation(ng/mL) as a function of time from a single dose pharmacokinetic studyin healthy human subjects administered the present combination dosageform of axelopran and oxycodone hydrochloride, co-administered the twocomponents as individual tablets and administered the componentsindividually.

FIG. 7 shows a powder X-ray diffraction pattern of a combination dosageform of axelopran sulfate (10 mg label claim) and oxycodonehydrochloride controlled-release tablet (20 mg label claim) FormulationA obtained with a Bruker D8-Advance X-ray diffractometer using Cu—Kαradiation (λ=1.54051 Å) with output voltage of 45 kV and current of 40mA.

FIG. 8 shows the weight change of a spray coated film of axelopransulfate and polyvinyl alcohol in a 4:1 wt/wt ratio subjected to 70%relative humidity at 25° C.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term ‘solid dosage form’ refers to a pharmaceuticalformulation in solid form for oral administration to a patient. The termcomprises pills, tablets, beads, beadlets, microparticulates, andcapsules. In particular, the term bead as used herein encompassesbeadlets, microparticulates, and the like.

As used herein, the term ‘modified release’ form refers to a formulationof a drug product that alters the timing and/or rate of release of theactive drug substance. The term ‘modified release’ form encompassesforms that are variously described as controlled-release,sustained-release, extended-release, and long-acting.

As used herein, the term ‘immediate release’ form refers to aformulation designed to release the active drug immediately upon oraladministration. In immediate release formulations, no attempt has beenmade to modify the drug release rate.

In accordance with the present invention, a combination dosage form isprovided which includes a peripheral mu opioid receptor antagonist, suchas axelopran or a pharmaceutically acceptable salt thereof and an opioidanalgesic agent. The opioid analgesic agent may be present in a modifiedrelease pharmaceutical formulation designed to affect the rate ofrelease of the agent after administration to a patient, as definedherein. The opioid analgesic dosage form may also includeabuse-deterrent properties.

Suitable opioid analgesic agents for inclusion in the present inventioninclude oxycodone, hydrocodone, morphine, oxymorphone, andhydromorphone. Numerous controlled release or extended releaseformulations of these agents are available as commercial products or inearly or late-stage development. Examples of such agents include, butare not limited to:

oxycodone: OxyContin® (oxycodone hydrochloride controlled release,Purdue Pharma), Oxycodone DETERx™ (oxycodone, extended release,Collegium Pharma), Egalet-002 (oxycodone, extended release, EgaletCorporation),

hydrocodone: Hysingla™ ER (hydrocodone bitartrate, extended release,Purdue Pharma), Zohydro™ ER (hydrocodone bitartrate, extended release,Zogenix, Inc.), Vantrela™ (hydrocodone bitartrate, extended release,Teva Pharmaceutical Industries, Ltd)

morphine: Egalet-001 (Egalet Corporation), ER morphine (InspirionDelivery Technologies), MS Contin® (Purdue Pharma)

oxymorphone: Opana® ER (oxymorphone hydrochloride, extended release,Endo Pharmaceuticals), Col-172 (Collegium Pharma)

hydromorphone: Exalgo® (hydromorphone hydrochloride, extended release,Mallinckrodt Pharmaceuticals)

Additional examples include products which also incorporate a non-opioidanalgesic agent, in particular acetaminophen. Examples of suchcombinations include, but are not limited to:

Xartemis™ XR (oxycodone hydrochloride and acetaminophen, extendedrelease, Mallinckrodt Pharmaceuticals)

MNK-155 (hydrocodone bitartrate and acetaminophen, controlled release,Mallinckrodt Pharmaceuticals)

As described in U.S. Pat. No. 7,943,772, axelopran sulfate forms astable crystalline form while amorphous axelopran is not sufficientlystable for use in a drug product. As described therein, the crystallineform is characterized by a powder X-ray powder diffraction (PXRD)pattern having two or more diffraction peaks at 2θ values selected from6.58±0.20, 7.52±0.20, 9.35±0.20, 14.69±0.20, 16.01±0.20, 17.45±0.20,17.99±0.20, 18.62±0.20, 19.76±0.20, 21.11±0.20, 22.07±0.20, 23.18±0.20,23.74±0.20, 24.56±0.20, 25.63±0.20, 26.45±0.20, 27.86±0.20, 28.31±0.20,29.54±0.20, 30.59±0.20, 31.58±0.20, 33.89±0.20, and 36.02±0.20. Inparticular, stability of the axelopran sulfate crystalline form ataccelerated conditions has been demonstrated. Thus, it is desirable forany drug product to comprise axelopran in a crystalline form.

The provision of stable combination dosage forms including axelopran ismade possible by the discovery by the present inventors of the keyrequirements for the conversion of amorphous axelopran to crystallineaxelopran during or after any process that may initially form amorphousaxelopran. The choice of excipients in the coating solution was found tobe one factor. As shown in Example 10 below, conventional coatingpolymers do not lead to films that are sufficiently stable when testedat accelerated conditions. The example also shows that the ratio ofaxelopran to excipients is another critical factor.

The present inventors have further demonstrated that high moisturecontent promotes crystallization as demonstrated in Example 11 and FIG.8. A spray coated film of axelopran sulfate and polyvinyl alcohol in a4:1 wt/wt ratio was subjected to 70% relative humidity for 48 hours at25° C. The weight gain over the first two hours may be attributed toabsorption of moisture by amorphous axelopran sulfate. The weight lossover the subsequent time period may be attributed to the crystallizationof axelopran sulfate which releases the moisture absorbed by theamorphous form.

Oxidation has been identified as the main degradation pathway ofamorphous axelopran. Therefore, in any process of preparing a layercontaining crystalline axelopran from a solution in which the compoundis amorphous, it is useful to control oxidation before crystallizationtakes place. While high moisture content was found to promotecrystallization, at the same time, high moisture content promotesoxidation. One viable option, then, is to use an inert gas, such asnitrogen or argon, as an atomizing gas during a spray coating process toreduce or eliminate oxidation. Another option is to use an antioxidantin the formulation to control oxidation during spray coating.

Based on these discoveries, a solid composition that promotescrystallization of axelopran comprises axelopran sulfate and a filmforming polymer. In another aspect, the solid composition comprisesaxelopran sulfate, a plasticizer, and optionally an antioxidant.

The solid composition may be prepared from an aqueous solution or acombination of water with a lower alcohol, for example, up to about 40%methanol or ethanol in water, but is preferably prepared from anaqueous-based solution. Examples of film forming polymers known in theart include, but are not limited to, polyvinyl alcohol,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose, copovidone, and combinations thereof. However,as exemplified below, it has been determined that not all film formingpolymers are equally compatible with promoting axelopran crystallizationand/or chemical stability. In a particular aspect, the film formingpolymer is polyvinyl alcohol. Hydrophilic plasticizers known in the artinclude, but are not limited to, polyethylene glycols, glycerin,polyethylene glycol monomethyl ether, propylene glycol, triacetin, andsorbitol sorbitan solution. It has further been determined, that thechoice of plasticizer is also important. Polyethylene glycol 3350 isparticularly useful in the present formulation. Polyethylene glycol isan ethylene glycol polymer having an average molecular number of 3350.Antioxidants include, but are not limited to, ascorbic acid, propylgallate, sodium sulfite, sodium metabisulfite, sodium bisulfite,thioglycerol, thioglycollic acid, butylated hydroxytoluene, butylatedhydroxyanisole, and combinations thereof. A preferred antioxidant isascorbic acid.

In the solid composition that promotes crystallization, axelopransulfate is present in an amount ranging from about 50% to about 95% byweight, including from about 50% to about 85% by weight, and from about50% to about 70% by weight. The film forming polymer, such as polyvinylalcohol, is present in an amount between about 5% and about 50% byweight, including between about 10% and about 50% by weight, betweenabout 10% and about 35% by weight, and between about 12% and about 25%by weight. The plasticizer, such as polyethylene glycol 3350, is presentin an amount between about 0% and about 45% by weight, including betweenabout 5% and about 30% by weight, and between about 12% and about 25% byweight. The optional antioxidant, such as ascorbic acid, is present inan amount between about 0% and about 10% by weight, including betweenabout 0.5% and about 10% by weight, and between about 2% and about 6% byweight.

In one aspect, therefore, the invention provides a solid compositioncomprising:

(a) between about 50% and about 95% by weight axelopran sulfate,

(b) between about 5% and about 50% by weight polyvinyl alcohol,

(c) between about 0% and about 45% polyethylene glycol 3350, and

(d) between about 0% and about 10% ascorbic acid.

In another aspect, the invention provides a solid compositioncomprising:

(a) between about 50% and about 70% by weight axelopran sulfate,

(b) between about 10% and about 50% by weight polyvinyl alcohol,

(c) between about 5% and about 30% polyethylene glycol 3350, and

(d) between about 0.5% and about 10% ascorbic acid.

In yet another aspect, the solid composition comprises:

(a) between about 50% and about 70% by weight axelopran sulfate,

(b) between about 12% and about 25% by weight polyvinyl alcohol,

(c) between about 12% and about 25% polyethylene glycol 3350, and

(d) between about 2% and about 6% ascorbic acid.

As described above, the solid composition of the invention may beprepared from an aqueous solution or suspension, in particular asolution or suspension comprising axelopran sulfate, polyvinyl alcohol,optionally polyethylene glycol 3350 and optionally ascorbic acid.Typically, the solid composition is prepared from an aqueous solution.In the aqueous solution, axelopran, polyvinyl alcohol, optionalpolyethylene glycol 3350 and optional ascorbic acid are typicallypresent in the same ratio as in the solid composition. The components ofthe solid composition, i.e. the non-aqueous components of the solution,collectively termed the ‘solid content’, may comprise between about 1%and about 50%, typically between about 5% and about 15%, for example,about 10%, of the aqueous solution, the remainder typically beingpurified water.

In another aspect, therefore, the invention provides an aqueous solutioncomprising between about 5% and about 15% solid content, wherein thesolid content comprises axelopran sulfate, polyvinyl alcohol, optionalpolyethylene glycol 3350, and optinal ascorbic acid in the ratios of thesolid composition described above.

The solid composition may constitute one layer, i.e. the active coatinglayer, of a combination dosage form, or may form a coating on an inertsolid tablet to provide axelopran as a monotherapy. Alternatively thesolid composition may be prepared as a solid beadlet which, for example,may be combined with beadlets of a different agent in a combinationdosage form.

In one aspect, the invention provides a combination dosage formcomprising the solid composition of the invention as an active coatinglayer, equivalently termed a drug overcoat layer, on an opioid analgesicdosage form. In one aspect, the combination dosage form comprisescrystalline axelopran sulfate. In one aspect, the drug overcoat layercomprising crystlaline axelopran sulfate further comprises a filmforming plymer and a plasticizer. The active coating layer comprisingaxelopran is designed to release drug in an immediate release pattern.

In another aspect, the invention provides a combination dosage formcomprising an opioid analgesic solid dosage form and a drug overcoatlayer comprising:

(a) between about 50% and about 70% by weight axelopran sulfate,

(b) between about 10% and about 50% by weight polyvinyl alcohol,

(c) between about 5% and about 30% polyethylene glycol 3350, and

(d) between about 0.5% and about 10% ascorbic acid.

In yet another aspect, the drug overcoat layer comprises:

(a) between about 50% and about 70% by weight axelopran sulfate,

(b) between about 12% and about 25% by weight polyvinyl alcohol,

(c) between about 12% and about 25% polyethylene glycol 3350, and

(d) between about 2% and about 6% ascorbic acid.

As described in the examples below, a particularly useful active drugcoating layer comprises about 68% axelopran sulfate by weight, about 14%polyvinyl alcohol by weight, about 14% polyethylene glycol 3350 byweight, and about 4% ascorbic acid by weight, which corresponds to aweight ratio of axelopran free base equivalent:polyvinylalcohol:polyethylene glycol 3350:ascorbic acid of 12:3:3:1.

Optionally, the combination dosage form further comprises a subcoatlayer between the active coating layer and the opioid dosage form. It isconvenient to employ the same film forming polymer and plasticizer inthe subcoat layer as in the active coating. In a particular aspect, thecombination dosage form of the present invention includes an optionalsubcoat layer comprising polyvinyl alcohol and polyethylene glycol 3350,for example in about a 1:2 ratio of polyvinyl alcohol to polyethyleneglycol 3350.

The active coating may be prepared from an aqueous coating solutiondescribed above as the aqueous solution for the preparation of thepresent solid composition. A coating solution for applying the optionalsubcoat comprises between about 5% and about 15% subcoat components,i.e. polyvinyl alcohol and polyethylene glycol 3350, with the remainderbeing purified water.

The present combination dosage form may be prepared by applying theaqueous coating solution described herein onto an optionally subcoatedopioid tablet, pill, bead, beadlet, or capsule. The process of preparingthe active coating layer and the optional subcoat layer may utilize apan coater or fluid bed or wurster coating column. For example, asdescribed in the appended examples, a pan coater may be used to spraycoat a subcoat coating solution and subsequently the aqueous activelayer coating solution onto opioid tablets. The process is typicallyperformed at an exhaust temperature of about 40° C. Spray coating ontobeads with a characteristic diameter of about 500 μm using a fluid bedhas also been demonstrated.

In one aspect, therefore, the invention provides a method of preparing acombination dosage form, the method comprising (a) providing an opioidanalgesic agent in a solid dosage form, and (b) coating the solid dosageform with a drug overcoat layer comprising axelopran sulfate andpolyvinyl alcohol.

In a further aspect, a method of preparing a combination dosage formcomprises: (a) providing an opioid analgesic agent in a solid dosageform, and (b) applying an aqueous coating solution comprising axelopransulfate, polyvinyl alcohol, polyethylene glycol 3350, and optionallyascorbic acid. In yet another aspect, the method further comprisesapplying an aqueous subcoat coating solution comprising polyvinylalcohol and polyethylene glycol 3350 onto the opioid solid dosage formbefore applying the active layer coating solution.

It has been discovered that subjecting a layer comprising axelopransulfate in an amorphous form or in a form in which crystallization isincomplete to high relative humidity, for example between about 70% andabout 86% relative humidity at a temperature between about 20° C. andabout 45° C. results in conversion of amorphous axelopran sulfate to thecrystalline form. In particular, it has been discovered that the abilityto crystallize axelopran post-coating is enhanced by the specificformulation of the solid layer disclosed herein.

The spray coating process parameters described below in Examples 2, 3,and 7 in which an aqueous solution is sprayed at 40° C. or 45° C.provide the conditions conducive to formation of crystalline axelopransulfate, as demonstrated by the powder X-ray diffraction pattern of acombination dosage form prepared by the exemplified spray coatingprocess shown in FIG. 7.

Furthermore, a combination dosage form prepared by a process such asthat described in the examples has been shown to be stable upon storage.After three months at accelerated conditions of 40° C. and 75% relativehumidity, no significant changes in axelopran content and impurityprofile, as well as in the dissolution profile, were observed in acombination dosage of axelopran sulfate and oxycodone hydrochlorideindicating good stability of the combination dosage form, which furthermay be taken as evidence of crystallinity.

Axelopran has been shown to be effective at ameliorating the symptoms ofopioid-induced constipation at low dosages. By suitably adjusting theprocessing conditions, a combination dosage form containing betweenabout 2 mg and about 30 mg axelopran per unit dosage may be preparedwith good content uniformity. For example, the inventors havedemonstrated a combination dosage form of about 10 mg axelopran coatedonto 20 mg oxycodone hydrochloride controlled release tablets and onto10 mg oxymorphone hydrochloride extended release tablets with a relativestandard deviation of axelopran content of less than about 5%.

The present combination dosage form comprising an axelopran activecoating and a modified release opioid exhibits immediate release ofaxelopran and extended release of the opioid. For example, the in vitrodrug dissolution profile of an approximate 10 mg coating of axelopranovercoat on a controlled release oxycodone hydrochloride tablet (FIG. 1Aand FIG. 1B) shows essentially all of the axelopran was released in thefirst quarter hour while the oxycodone was released gradually over 12hours. Furthermore, the in vitro drug dissolution profile of the 10 mgaxelopran coated oxycodone hydrochloride tablet that had been stored at40° C. and 75% relative humidity was unchanged from the dissolutionprofile of time-zero tablets. Similarly, in vitro dissolution ofaxelopran coated oxymorphone hydrochloride extended release tabletsdemonstrates essentially all of the axelopran was released in the firstquarter hour while the oxymorphone was released gradually over 12 hours(FIG. 2A and FIG. 2B).

In addition, the present combination dosage form has been shown in vivoto provide systemic exposure of the two components consistent with theexposures observed on co-administration of the two components inseparate dosage forms. A pharmacokinetic study of axelopran coatedoxycodone hydrochloride tablets and axelopran coated oxymorphonehydrochloride tablets in dogs is described in Example 8. Littledifference is seen in the systemic exposure of oxycodone whenadministered as the combination dosage form with axelopran, as comparedwith the exposure from administration of axelopran and oxycodone inseparate dosage forms, and with administration of oxycodone alone, inFIG. 3A. Systemic exposure of axelopran from the combination dosage formwith oxycodone is shown to be consistent with exposure fromadministration in separate dosage forms and from administration ofaxelopran alone in FIG. 3B. Consistent exposures were also observed forthe combination dosage form of axelopran and oxymorphone as illustratedin FIG. 4A and FIG. 4B.

The present combination dosage form of axelopran and oxycodone was alsostudied in healthy human subjects. Taking co-administration of theindividual tablets as the reference product, the combination dosage formof 10 mg axelopran and 20 mg oxycodone hydrochloride demonstrated totalexposure of axelopran within 16% of the reference value and totalexposure of oxycodone within 5% of the reference value in healthy humansubjects. Furthermore, the oxycodone exposure satisfied the US FDAguidelines for bioequivalence as compared with the reference product.Also, the total exposure of oxycodone from the combination wasequivalent to the exposure experienced when oxycodone was administeredalone. As illustrated in FIG. 5, the combination dosage form ofaxelopran and oxycodone did not alter the systemic exposure ofoxycodone.

Utility

The opioid therapeutic agents such as oxycodone, hydrocodone, morphine,and oxymorphone, are widely used for the treatment of pain includingsevere pain, chronic pain, and non-cancer pain such as musculoskeletalpain and post-operative pain. As the combination dosage form ofaxelopran and an opioid analgesic agent is expected to provideequivalent exposure of the opioid after oral administration, the presentcombination dosage form is expected to be useful for the treatment ofpain.

In one aspect, therefore, the invention provides a method of treatingpain in a mammal, particularly a human patient, the method comprisingadministering to the mammal a combination dosage form comprisingaxelopran and an opioid analgesic agent. In one aspect, the inventionprovides a method of treating pain comprising administering acombination dosage form comprising axelopran in an immediate releaseformulation and an opioid analgesic agent in a modified releaseformulation.

The mu opioid receptor antagonist axelopran has been shown to amelioratethe symptoms of opioid-induced constipation in patients on a stableopioid regimen, that is to reduce one of the distressing side effects ofopioid therapy. As the combination dosage form of axelopran and anopioid analgesic is also expected to provide equivalent exposure ofaxelopran as compared with administration of axelopran separately, thepresent combination is expected to be useful for the amelioration ofopioid-induced gastrointestinal side effects. In another aspect,therefore, the present invention provides a method of ameliorating agastrointestinal side effect of opioid therapy in a mammal, inparticular a human patient, the method comprising administering to themammal a combination dosage form comprising axelopran and an opioidanalgesic agent.

EXAMPLES The following examples are offered to illustrate the invention,and are not to be construed in any way as limiting the scope of theinvention.

For all of the following examples, axelopran sulfate was synthesizedaccording to the process described in U.S. Pat. No. 7,943,772. Aclinical tablet formulation of axelopran was used as the test articlefor the in vivo studies. Oxycodone was provided as commercially-obtainedOxyContin® (oxycodone hydrochloride controlled release, 20 mg) tablets.According to the package insert, the tablets contain 20 mg oxycodone pertablet as the hydrochloride salt and the following inactiveingredients:butylated hydroxytoluene, hypromellose, polyethylene glycol400, polyethylene oxide, magnesium stearate, titanium dioxide,polysorbate 80, and red iron oxide. Oxymorphone was provided ascommercially-obtained Opana® ER (oxymorphone hydrochloride extendedrelease,10 mg) tablets. According to the package insert, the oxymorphonetablets contain 10 mg oxymorphone hydrochloride per tablet and thefollowing inactive ingredients: hypromellose, polyethylene oxide,polyethylene glycol, a-tocopherol, citric acid, polyvinyl alcohol,titanium dioxide, macrogel, talc, and FD&C yellow No. 6.

Example 1 Spray Coating Process

A Thomas Compu-Lab 19 inch pan coater was used to prepare thecombination dosage forms of Examples 2 and 3. Processing parametersoptimized for coating performance and efficiency are summarized in Table1.

TABLE 1 Processing Parameters Set I Set II Exhaust Temp (° C.)  40^(a) 40^(a) Solution Spray Rate (g/mL) 15 13 Atomizing Air Pressure (psi) 35^(b)  35^(b) Pan Speed (rpm) 15 15 Air Flow Rate (scfm) 170  170 Inlet Temp (° C.) 65 65 Gun to Bed Distance (inches)  7  7 ^(a)Range:35-50 ^(b)Range: 25-45

Example 2 Preparation of Combination Dosage Form of Axelopran (10 mg)and Oxycodone Hydrochloride (20 mg)

Placebo cores were manufactured to match the OxyContin® tablets and wereused as the main load of the substrate for the coating.

(a) Preparation of Subcoat

To prepare the coating solution, polyvinyl alcohol (40 g) was added toheated purified water USP. The mixture was stirred and heated todissolution and then polyethylene glycol 3350 (80 g) was added and themixture was stirred to dissolution. Purified water USP was added withstirring to provide a solution of approximately 10% solid content (i.e.,non-aqueous content; the solid content is not in solid form).

A total of approximately 4 kg of placebo cores and a small number ofOxyContin® tablets were spray coated with the subcoat solution accordingto the processing parameters of Table I Set Ito achieve an approximate3% weight gain of the sub-coat composition listed in Table 2.

TABLE 2 Sub-coat Formulation Composition Formulation CompositionComponent % wt Unit Dose (mg/Tab) Polyvinyl Alcohol, USP 33.3 1.56Polyethylene Glycol 3350, NF, EP 66.7 3.12

(b) Preparation of Active Coating Layer

Quantities of components to create active coating solutions for twoformulations are listed in Table 3. To prepare each active coatingsolution, polyvinyl alcohol was added to heated purified water USP. Themixture was stirred and heated to dissolution and then polyethyleneglycol was added, the mixture was stirred to dissolution, and ascorbicacid was added with stirring followed by axelopran sulfate. Purifiedwater USP was added with stirring to provide a coating solution ofapproximately 10% solid content (e.g., non-aqueous content; the solidcontent is not in solid form).

TABLE 3 Axelopran Drug Active Coating Layer Formulation CompositionsFormulation A Formulation B Unit Unit Dose Batch Dose Batch (mg/Quantity (mg/ Quantity Part^(a) Tab) (g) Part^(a) Tab) (g) Axelopransulfate 12 12.27 314.6 12 12.27 314.6 Ascorbic Acid, USP 1 0.83 21.4 21.67 42.7 Polyvinyl Alcohol, 3 2.5 64.1 3 2.5 64.1 USP PolyethyleneGlycol 3 2.5 64.1 6 5.0 128.2 3350 ^(a)Axelopran free base equivalent

Upon completion of the sub-coating, the sub-coated placebo cores andopioid tablets were retained in the pan coater and further spray coatedwith the active coating solution according to the processing parametersof Table 1 Set Ito achieve the target weight gain. Coated opioid tabletswere separated from coated placebo cores by the difference in color uponcompletion of the coating.

Example 3 Preparation of Combination Dosage Form of Axelopran (10 mg)and Oxymorphone Hydrochloride (20 mg)

Placebo cores were manufactured to match the Opana® ER tablets and wereused as the main load of the substrate for the coating.

(a) Preparation of Subcoat

A subcoat coating solution was prepared as in Example 2(a). A total ofapproximately 4 kg of placebo cores and a small number of Opana® ERtablets were spray coated according to the processing parameters ofTable I Set II resulting in an approximate 3% weight gain of thesub-coat composition listed in Table 2.

(b) Preparation of Active Coating Layer

Coating solutions for the two formulations of Table 3 were prepared asdescribed in Example 2(a). Upon completion of the sub-coating, thesub-coated placebo cores and opioid tablets were retained in the pancoater and further spray coated with the active coating solutionsaccording to the processing parameters of Table 1 Set Ito achieve thetarget weight gain. Coated opioid tablets were separated from coatedplacebo cores by the difference in color upon completion of the coating.

Example 4 Analysis of Drug Content Uniformity

The axelopran drug overcoated opioid tablets (n=10 tablets performulation) were analyzed for drug content potency and uniformity byhigh-pressure liquid chromatography (HPLC) with UV detection. Resultsfor the combination dosage forms prepared in Examples 2 and 3 arereported in Table 4.

TABLE 4 Axelopran Drug Content Potency and Uniformity Example 2oxycodone Example 3 oxymorphone Formu- Formu- Formu- Formu- lation Alation B lation A lation B Axelopran content 118.5% 125.7% 92.6% 94.1%(% Label claim)^(a) Axelopran uniformity 3.14% 3.26% 5.76% 4.94%(Relative standard deviation) ^(a)Label claim = 10 mg axelopran

Example 5 Drug Dissolution Profile

The axelopran coated opioid tablets of Examples 2 and 3 (n=6 tablets performulation) were tested for drug dissolution rate of the individualcomponents according to USP monograph 711 and in-house developedmethodologies. Sample aliquots were collected at 13, 30, 45, 60,minutes, and at 4 and 12 hour dissolution time points and analyzed byreverse-phase HPLC with UV detection. The dissolution rate results forthe individual components from the axelopran coated oxycodone tabletsare shown in Table 5 and in FIGS. 1A and 1B, while the analogousdissolution rate results for axelopran coated oxymorphone tablets areshown in Table 6 and in FIGS. 2A and 2B. In all cases, essentially allof the axelopran is observed to have dissolved by the first time pointof 0.25 hour while the controlled release opioid dissolved graduallyover 12 hours.

TABLE 5 In vitro Dissolution of Axelopran/Oxycodone Combination DosageForm Time (hr) % LC (Ave)^(a) % LC (% RSD)^(b) Example 2 Formulation AAxelopran 0 0 0 0.25 118 3.37 0.50 119 3.52 0.75 120 3.19 1.00 121 3.25Oxycodone 1 24 4.15 4 64 3.89 12 97 3.49 Example 2 Formulation BAxelopran 0 0 0 0.25 124 3.24 0.50 125 3.32 0.75 125 3.31 1.00 125 3.34Oxycodone 1 25 2.13 4 68 1.71 12 98 2.18 ^(a)% Label claim with respectto axelopran 10 mg ^(b)Relative Standard Deviation

TABLE 6 In vitro Dissolution of Axelopran/Oxymorphone Combination DosageForm Time (hr) % LC (Ave)^(a) % LC (% RSD)^(b) Example 3 Formulation AAxelopran 0 0 0 0.25 94 4.63 0.50 95 4.67 0.75 96 4.62 1.00 96 4.65Oxymorphone 1 29 1.93 4 72 2.09 6 89 1.97 10 101 1.57 14 101 1.75Example 3 Formulation B Axelopran 0 0 0 0.25 94 4.63 0.50 95 4.67 0.7596 4.62 1.00 96 4.65 Oxymorphone 1 31 6.18 4 76 5.52 6 92 3.43 10 991.25 14 98 1.17 ^(a)% Label claim with respect to axelopran 10 mg^(b)Relative Standard Deviation

Example 6 Stability Study

Samples of an axelopran sulfate/oxycodone hydrochloride combinationdosage form with the active coating layer formulation of Example 2Formulation A stored at accelerated conditions of 40° C. and 75%relative humidity (RH) were analyzed by HPLC for axelopran content andimpurity profile as shown in Table 7 and for dissolution rate as shownin Table 8.

TABLE 7 Axelopran Assay and Impurities (n = 3) T = 1 Month T = 3 Month T= 0 40° C./75% RH 40° C./75% RH RRT % a/a % a/a % a/a 0.80 0.201 0.1890.193 0.92 0.021 0.050 0.071 1.15 0.069 0.092 0.098 1.35 0.222 0.2320.237 1.44 0.092 0.110 0.103 % LC % LC % LC Axelopran 96.18 93.01891.187

TABLE 8 In vitro Dissolution of Axelopran/Oxycodone Combination DosageForm (n = 6) T = 1 Month T = 3 Month T = 0 40° C./75% RH 40° C./75% RHTime % LC % LC % LC % LC % LC % LC (hr) (Ave)^(a) (% RSD)^(b) (Ave)^(a)(% RSD)^(b) (Ave)^(a) (% RSD)^(b) Axelopran 0 0 0 0 0 0 0 0.25 94.2 5.5392.2 3.05 95.4 6.06 0.50 95.3 5.23 93.0 2.95 96.9 6.13 0.75 95.6 5.1893.4 2.95 97.8 5.91 1.00 95.9 5.10 93.8 2.93 98.3 5.83 Oxycodone 1 25.32.78 23.4 5.35 23.9 5.13 4 67.9 3.15 67.0 2.79 12 98.1 3.44 97.0 5.5297.4 2.48 ^(a)% Label claim with respect to axelopran 10 mg ^(b)RelativeStandard Deviation

Example 7 Preparation of Axelopran Coated Beads

The feasibility of preparing a combination dosage form on a solid dosageform composed of beads was demonstrated by coating sugar spheres havinga characteristic diameter of 500 μm.

The composition to prepare a nominal 10 mg axelopran coating per 450 mgof beads is listed in Table 9.

TABLE 9 Axelopran coated bead batch composition Ingredient w/w % BatchQuantity (g) Subcoat Sugar Spheres 30/35 87.24 174.50 Polyvinyl alcohol,USP 2.91 5.82 Polyethylene glycol 3350 5.81 11.63 Purified Water —157.00 Total 95.96 192.00 Axelopran Drug Overcoat Subcoated sugarspheres (beads) 95.96 192.00 Axelopran Sulfate 2.75 5.50 Ascorbic acid0.18 0.36 Polyvinyl alcohol, USP 0.56 1.12 Polyethylene glycol 3350 0.561.12 Purified Water — 72.90 Total 100 200.020

Three coating runs were performed:

A. Batch Quantity 200 g with Subcoat

A subcoat coating solution and axelopran active coating layer solutionwere prepared according to the process described in Example 2. Sugarbeads were loaded into the bowl of a Glatt mini fluid bed and warmed toabout 45° C. The subcoat coating solution was sprayed onto the beads ata spray rate of 0.6 g/min until a 10% weight gain was achieved. Uponcompletion of the subcoating, the active coating layer solution wassprayed onto the subcoated sugar beads at a spray rate of 0.6 g/min. Theproduct temperature was maintained at about 45° C. in the fluid bed withatomization air pressure of 0.8 to 1.0 bar. Upon completion ofdeposition of the active coating layer, the beads were dried at 45° C.for 10 min before discharging.

B. Batch Quantity 200 g without Subcoat

An active coating layer solution of composition equivalent to thatdescribed in Table 8 was sprayed directly onto sugar beads as describedabove.

C. Batch Quantity 2 kg with Subcoat

Two batches of axelopran coated beads denoted C-1 and C-2, were preparedfrom compositions with batch quantity 10 times the quantities listed inTable 8 using a Glatt GPCG-3 fluid bed. Typical processing parametersare listed in Table 10.

TABLE 10 Fluid Bed Processing Parameters (2 kg batch) Column Height (mm)35 Inlet Temp (° C.) 52 Outlet Temp (° C.) 45 Product Temp (° C.) 45Solution Spray Rate (g/min) 4.0 Atomizing Air Pressure (psi) 30 OutletAir Control Flap (%) 40

The resulting beads were tested for content uniformity and maindegradant.

TABLE 11 Content uniformity and purity Batch A Batch B Batch C-1 BatchC-2 Axelopran content 97.7% 92.0% 95.0% 95.0% (% Label claim)^(a)Axelopran uniformity 0.30% 0.26% 0.76% 1.27% (Relative standarddeviation) Main Degradant 0.094 0.37 Not Not (% area/area) determineddetermined ^(a)Label claim based on 10 mg dose

Example 8 Pharmacokinetics and Relative Bioavailability in Dogs

A single dose, four period, cross over pharmacokinetic study in fastedbeagle dogs (6 male dogs per group) was conducted to assesspharmacokinetic characteristics and relative biovailability of axelopranand opioid (oxycodone or oxymorphone) following oral administration ofthe present combination dosage form, co-administration of the individualcomponents, and the individual dosage form of each component.

The combination dosage form of Example 2 Formulation A (11.85 mgaxelopran, 19.42 mg oxycodone per tablet) and individual tabletsaxelopran (10.21 mg), oxycodone (19.42 mg) were used for theaxelopran/oxycodone study. The combination dosage form of Example 3Formulation A (9.26 mg axelopran, 10.39 mg oxymorphone) and individualtablets axelopran (10.21 mg), oxymorphone (10.39 mg) were used for theaxelopran/oxymorphone study. A washout period between each phase of atleast 5 days was observed. The dogs received an intramuscularpentagastrin (6 μg/kg) pretreatment to reduce stomach pH.

Plasma profiles of axelopran and opioid from the pharmacokinetic studiesare shown in FIGS. 3A and 3B (oxycodone) and FIGS. 4A and 4B(oxymorphone), respectively.

Example 9 Pharmacokinetics and Relative Bioavailability in Healthy HumanSubjects

A randomized, single-dose, open-label, four treatment period foursequence cross over study of the relative bioavailability of axelopranand oxycodone after oral administration as the present combinationdosage form, after co-administration of the individual components, andafter administration of the individual dosage form of each component wasstudied in healthy human subjects. Naltrexone was administered 15 and 3hours prior to and 9 and 21 hours after administration of each treatmentto block the adverse effects of the opioid. A seven day washout periodbetween each period was observed. The number of subjects who completedat least one period was 28 with 26 subjects completing all four studyperiods.

Overcoated combination tablets (9.66 mg axelopran, 19.42 mg oxycodoneper tablet) were prepared according to the process of Example 2,axelopran layer in formulation A of Table 3. Individual tabletsaxelopran (10.21 mg), oxycodone (19.42 mg) were used for the study.

Pharmacokinetic (PK) parameters were determined by non-compartmentalanalysis using WinNonlin Version 6.2.1 (Pharsight, St. Lous, Mo.) Thefollowing PK parameters were reported:

-   -   C_(max): maximum concentration in plasma    -   AUC_(0-last): area under the concentration-time curve from time        of dosing to last measureable concentration    -   AUC_(0-∞): area under the concentration-time curve extrapolated        to infinity

Relative bioavailability for oxycodone and axelopran for the combinationdosage as compared with the co-administration of the individualcomponents is given in Tables 12 and 14, respectively. The relativebioavailability of oxycodone for combination dosage compared withoxycodone alone is given in Table 13. Plasma exposures of oxycodone andaxelopran are shown in FIG. 5 and FIG. 6, respectively.

The study demonstrated that the combination dosage form of axelopran andoxycodone provided clinically equivalent exposures to oxycodone andaxelopran relative to co-administration of individual tablets. Theoxycodone pharmacokinetic parameters C_(max), AUC_(0-last), andAUC_(0-∞) geometric mean ratios and the associated confidence intervalsare within 80% to 125% of the reference product. The C_(max),AUC_(0-last), and AUC_(0-∞) geometric mean ratios for axelopran from thecombination dosage with respect to co-administration of individualtablets are approximately 85%.

TABLE 12 Relative Bioavailability Of Oxycodone For Combination DosageForm Compared With Co-Administration Of Individual Components C_(max)AUC_(0-last) AUC_(0-∞) (ng/mL) (ng*hr/mL) (ng*hr/mL) Oxycodone +Mean^(a) 19.6 218 220 axelopran^(c) Co-administration (Referenceproduct) Oxycodone/ Mean^(a) 20.0 209 212 axelopran^(d) Combinationdosage form % Ref 101.9 96.0 96.0 90% CI^(b) 95.2-109.2 92.7-99.592.6-99.5 ^(a)Geometric least squares mean from linear mixed effectsanalysis ^(b)90% Confidence Interval of the ratio ^(c)N = 27 for C_(max)and AUC_(0-last), N = 26 for AUC_(0-∞) ^(d)N = 27 for C_(max),AUC_(0-last), and AUC_(0-∞)

TABLE 13 Relative Bioavailability Of Oxycodone For Combination DosageForm Compared With Oxycodone Alone^(a) C_(max) AUC_(0-last) AUC_(0-∞)(ng/mL) (ng*hr/mL) (ng*hr/mL) Oxycodone tablet^(c) Mean^(a) 19.1 208 211(Reference product) Oxycodone/ Mean^(a) 20.0 209 212 axelopran^(d)Combination dosage form % Ref 104.3 100.4 100.3 90% CI^(b) 98.1-111.096.5-104.4 96.4-104.3 ^(a)Geometric least squares mean from linear mixedeffects analysis ^(b)90% Confidence Interval of the ratio ^(c)N = 26 forC_(max), AUC_(0-last), and AUC_(0-∞) ^(d)N = 27 for C_(max),AUC_(0-last), and AUC_(0-∞)

TABLE 14 Relative Bioavailability Of Axelopran For Combination DosageForm Compared With Co-Administration of Individual Components^(a)C_(max) AUC_(0-last) AUC_(0-∞) (ng/mL) (ng*hr/mL) (ng*hr/mL) Oxycodone +Mean^(a) 3.09 29.4 30.6 axelopran^(c) Co-administration (Referenceproduct) Oxycodone/ Mean^(a) 2.60 25.3 26.3 axelopran^(c) Combinationdosage form % Ref 84.2 86.0 86.1 90% CI^(b) 70.1-101.2 80.2-92.280.3-92.4 ^(a)Geometric least squares mean from linear mixed effectsanalysis ^(b)90% Confidence Interval of the ratio ^(c)N = 27 forC_(max), AUC_(0-last), and AUC_(0-∞)

Example 10 Excipient Compatibility Study

The compatibility of axelopran with four compositions of commercialcoating materials was studied as a function of ratio of coating materialto axelopran. Mixtures of axelopran sulfate and the materials of Table15 were dried at 40° C. in weighing boats to form films. Chemicalstability of the films stored at accelerated conditions of 40° C. and88% relative humidity for 2 weeks were analyzed by HPLC.

TABLE 15 Coating materials Material No. Material Name ChemicalCompositions 1 Opadry II Pink Polyvinyl alcohol, titanium dioxide, PEG,Talc, yellow iron oxide, red iron oxide 2 Opadry II PVA Polyvinylalcohol, Talc, PEG^(a) 3350, Base Clear Polysorbate 80 3 HPMC/Triacetin/HPMC^(b), Triacetin, Talc Talc 4 HPMC/PEG HPMC^(b), PEG 400^(a)polyethylene glycol ^(b)hydroxypropylmethyl cellulose

TABLE 16 Axelopran Assay Material Ratio of Coating Material T = 0 T = 2Weeks No. to Axelopran^(a) (% Area) (% Area) Axelopran N/A 99.70 N/A 11/1 98.83 94.41 3/1 97.97 86.48 6/1 98.09 75.25 2 1/1 98.72 93.06 3/197.54 77.00 6/1 97.89 47.17 3 1/1 98.43 73.72 3/1 97.72 55.11 6/1 97.646.69 4 1/1 98.06 89.67 3/1 96.29 14.62 6/1 95.63 25.60 ^(a)Relative toaxelopran free base equivalent

Example 11 Moisture Sorption Analysis of Axelopran Film

An aqueous solution of axelopran sulfate and polyvinyl alcohol in a 4:1wt/wt ratio at 2.5% solid loading was spray coated onto a jacketed glasssurface at 60° C. A small piece of film was placed in a moisturesorption analyzer (SGA-100, VTI Corp. Hialeah, Fla.). The humidity wasset to about 0% relative humidity (RH) for 10 min and then raised to 70%RH for 48 hours. The temperature was set at 25° C. As shown in FIG. 8,the film increased in weight for the first two hours and began to loseweight after the initial gain. The weight gain over the first two hoursmay be attributed to absorption of moisture by amorphous axelopransulfate. The weight loss over the subsequent time period may beattributed to the crystallization of axelopran sulfate which releasesthe moisture absorbed by the amorphous form. The net gain in film weightmay be attributed to moisture sorption by the polyvinyl alcohol.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1-19. (canceled)
 20. A method of preparing a combination dosage formcomprising a solid dosage form comprising an opioid analgesic agent, andan immediate release portion comprising crystalline axelopran sulfate,wherein the immediate release portion is a drug overcoat layer on thesolid dosage form and wherein the drug overcoat layer comprises: (i)between 50% and 70% by weight axelopran sulfate, (ii) between 12% and25% by weight polyvinyl alcohol, (iii) between 12% and 25% by weightpolyethylene glycol 3350, and (iv) between 2% and 6% by weight ascorbicacid, the method comprising: (a) providing an opioid analgesic agent ina solid dosage form, and (b) coating the solid dosage form with anaqueous solution wherein the non-aqueous components of the solutioncomprise: (b1) between 50% and 70% by weight axelopran sulfate, (b2)between 12% and 25% by weight polyvinyl alcohol, (b3) between 12% and25% by weight polyethylene glycol 3350, and (b4) between 2% and 6% byweight ascorbic acid.
 21. (canceled)
 22. The method of claim 20 furthercomprising coating the opioid solid dosage form with a subcoating layercomprising polyvinyl alcohol and polyethylene glycol onto the opioidsolid dosage form before applying the drug overcoat layer comprisingaxelopran.
 23. The method of claim 20 wherein the coated solid dosageform obtained after step (b) is exposed to between 70% and 86% relativehumidity at a temperature between 20° C. and 45° C. until axelopransulfate is converted to crystalline form. 24-25. (canceled)
 26. Themethod of claim 20 wherein the opioid analgesic agent is in a modifiedrelease formulation.
 27. The method of claim 20 wherein the solid dosageform comprising the opioid analgesic agent is a tablet.
 28. The methodof claim 20 wherein the solid dosage form comprising the opioidanalgesic agent is composed of beads.
 29. The method of claim 20 whereinthe solid dosage form comprising the opioid analgesic agent is a pill.30. The method of claim 20 wherein the opioid analgesic agent isoxycodone or oxymorphone.
 31. The method of claim 20, wherein a pancoater, a fluid bed or a wurster coating column is used in step (b). 32.The method of claim 20, wherein a pan coater is used in step (b) forspray coating.
 33. The method of claim 20, wherein in step (b), theaqueous solution is sprayed at about 40° C.